This Mentored Clinical Scientist Development Award (K08) will allow me to build a career as a successful independent physician-scientist devoted to the study of migraine and other headache disorders. Drs. Russo and Hammond will be my mentors at The University of Iowa. My long-term career goal is to identify therapeutic targets to prevent the development of chronic migraine based on biological information gained from the study of animal models. My immediate goal is to identify the mechanisms of interaction between obesity and migraine that lead to the development of chronic migraine. The objective of this proposal is to test the concept that calcitonin gene-related peptide (CGRP) represents a biological link between obesity and migraine. CGRP plays an important role in migraine and possibly in obesity. Our central hypothesis is that obesity in mice increases CGRP production and activity in trigeminal pathways, which leads to enhanced pain and other phenotypic correlates of migraine. A set of 3 complementary, but independent, specific aims are proposed. In Aim 1 we will use behavioral and immunohistochemical studies to establish the influence of obesity in the trigeminal nociceptive pathway, which is central in migraine pathophysiology. In Aim 2 we will employ molecular biology techniques to determine the effect of obesity on CGRP levels and receptor activity. In Aim 3 we will use a behavioral and pharmacological approach to assess whether obesity enhances migraine-like features of a transgenic mouse model of migraine. The results of these translational studies will provide fundamental knowledge necessary for future human studies. A better understanding of the interaction between obesity and migraine will have a significant impact in patient care. The objective of this proposal is highly relevant to the mission of the NINDS as it seeks to reduce the burden of migraine, a neurological disease with a prevalence of 12% in the general population worldwide. The identification of factors that contribute to the development of chronic migraine, and their mechanisms of action, will allow a preventive therapeutic approach. This will eventually lead to a lower prevalence of chronic migraine and a have a positive impact in our society. Public Health Relevance: Migraine is a common, disabling disorder that is aggravated by obesity. Both conditions represent serious public health problems worldwide, with a high cost to society. Understanding the way obesity and migraine interact is important to develop especific treatments to prevent the progression to chronic migraine. These studies will be the first to address the molecular basis of the association between obesity and migraine.